miR-22 inhibition reduces hepatic steatosis via FGF21 and FGFR1 induction

Abstract Background & Aims Metabolism supports cell proliferation and growth. Surprisingly, tumor suppressor miR-22 is inducible by metabolism stimulators like bile acids. Thus, this study examines whether miR-22 can be a metabolic silencer. Methods The relationship between miR-22 and fibroblast growth factor 21 (FGF21) and its receptor FGFR1 expression was studied in cells and fatty livers obtained from patients and mouse models. We evaluate the effect of a miR-22 inhibitor and in combination with obeticholic acid (OCA) in steatosis treatment. Results The levels of miR-22 and FGF21, FGFR1, as well as PGC1α were inversely correlated in human and mouse fatty livers, suggesting that hepatic miR-22 acts as a metabolic silencer. Indeed, miR-22 reduced FGFR1 by direct targeting and decreased FGF21 by reducing the occupancy of PPARα and PGC1α to their binding motifs. In contrast, a miR-22 inhibitor increases hepatic FGF21 and FGFR1, leading to AMPK and ERK1/2 activation, which was effective in treating alcoholic steatosis in mouse models. The farnesoid x receptor (FXR) agonist OCA induced FGF21 and FGFR1 as well as their inhibitor miR-22. A miR-22 inhibitor, OCA, and a combination of both were all effective in treating diet-induced steatosis, and the combined treatment produced the best effect on improving insulin sensitivity, releasing glucagon-like peptide 1, and reducing hepatic triglyceride in obese mice. Conclusion Novel data uncover the mechanisms by which miR-22 reduces FGF21 and FGFR1. Hepatic miR-22 overexpression leads to steatosis. The simultaneous induction of miR-22 as well as FGF21 and FGFR1 by metabolic stimulators may maintain FGF21 homeostasis and restrict ERK1/2 activation. Reducing miR-22 enhances hepatic FGF21 and activates AMPK, which can be a novel approach to treat steatosis and insulin resistance.